Nerve cells are the cells having a signal transduction function and their injury is expressed as the severe loss of cranial nerve function. In the central nerves of brain and spinal cord, regeneration of axon is hardly expected and, when nerve cells are injured or denatured, it is necessary to protect and to activate the nerve cells. As the biophylaxis function as such, the role of neurotrophic factors in charge of differentiation of nerve cells, survival maintenance, promotion of synapse function and regeneration/repair of injured nerve axon is essential.
In the neurotrophic factors, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), etc. constitute a neurotrophin family having not less than 50% of sequence homology where nerve growth factor (NGF) is a prototype. When neurotrophin secreted to outside of the cells is bound to high-affinity receptors (Trks) on nerve cell membranes, signals are transduced in three directions in the nerve cells. Via activation of MAP kinase signal transduction pathway including activation (phosphorylation) of MAP kinase (mitogen-activated protein (MAP) kinases/extracellular signal-regulated protein kinases 1/2 (ERK 1/2)) being one of the above, CREB (cAMP-response element binding protein) of transcription factor is activated whereupon many gene expressions are controlled. Accordingly, when the signal transduction via the MAP kinase signal transduction pathway is able to be activated, there is a possibility of its clinical application to nervous disorders caused by denaturation of nerve cells and cell death. There are also reports for the relation between the brain-derived neurotrophic factor (BDNF) and some diseases.
As a result of studies for genetic polymorphism of brain-derived neurotrophic factor (BDNF), there have been reports that the specific polymorphism relates to Parkinson's disease (refer to Non-Patent Document 1), to Alzheimer's disease (refer to Non-Patent Document 2), to depression (refer to Non-Patent Document 3), to bipolar depression (refer to Non-Patent Document 4) and to anxiety (refer to Non-Patent Document 5). There have been also reports that lowering of synapse function of gene-mutated mice of Huntington's disease is recovered by administration of the brain-derived neurotrophic factor (BDNF) (refer to Non-Patent Document 6) and that administration of an MAP kinase phosphorylation inhibitor induces the depressed state (refer to Non-Patent Document 7).
As will be noted from the examples of the above brain-derived neurotrophic factor (BDNF), neurotrophic factor shows a therapeutic effect to specific nerve diseases and has a sprouting and elongating action for axons. However, since neurotrophic factor is a high-molecular protein, there is a problem that, even when it is administered from periphery, it is unable to pass through a blood-brain barrier and hardly reaches the brain. Under such circumstances, there have been attempts for pharmaceutical agents which are low-molecular compounds and have neurotrophic factor-like activity activating the nerve cells and for pharmaceutical agents which promote the production and secretion of neurotrophic factor.
Until now, there have been proposals for the agents having a neurotrophic factor-like activity containing the compounds of predetermined general formulae (Patent Documents 1 and 2). There have been also proposals for the agents for accelerating the production/secretion of neurotrophic factor containing the compounds of predetermined general formulae (refer to Patent Documents 3 to 5) and for nerve regeneration promoters containing fatty acid compounds, salt thereof or prodrug thereof (refer to Patent Document 6).
There has been also a proposal for a medicament which contains the compound having a predetermined general formula and improves the lowering of response to GABA A receptor of astrocyte to prevent/treat the neurodegenerative disease, etc. (refer to Patent Document 7).
There has been also a proposal for an inducer of nerve cell differentiation where a medium-chain fatty acid having 6 to 10 carbons or methyl, ethyl, propyl or n-butyl ester of a medium-chain fatty acid having 6 to 10 chains is an active ingredient (refer to Patent Document 8).
There has been also mentioned that a fatty acid or a fatty acid ester has a neurotrophic factor-like activity (refer to Patent Document 9).
There has been also disclosed a fatty acid amide having tertiary amino group as a precursor of surface-active substances (refer to Patent Document 10).